AD is a progressive neurodegenerative disease which is the main factor of senile dementia, and the pathological cascade before appearance of clinical symptoms includes accumulation of extracellular Aβ→aggregation and accumulation of intracellular tau→neurodegeneration and neuronal death (the amyloid hypothesis). Therefore, AD is considered to begin with the accumulation of Aβ, and the fundamental treatment thereof requires removal of Aβ from the brain by inhibiting Aβ production, promoting degradation, suppressing aggregation, and removing aggregate deposit. Studies are being conducted competitively on a global scale for the development of such anti-Aβ drugs.
As a therapeutic drug for AD, some pharmaceutical agents such as Aricept (donepezil) and the like exist. However, they only have an effect of alleviating the disease state, and are not a fundamental therapeutic agent nor disease-modifying drug. On the other hand, in the research of Aβ metabolism, analysis of β- and γ-secretases related to the production system was conventionally performed. Therefore, the development of inhibitors or modulators targeting these enzymes also preceded in the drug discovery research of AD, and clinical trials were conducted for a plurality of pharmaceutical agents. However, the developments have been stopped one after another as the situation stands, due to the problems of side effects and the like. As for removal of aggregate deposit (Aβ vaccine therapy) and aggregation inhibitors, as other action sites, they were advanced to the clinical trial, but the development thereof was forced to be discontinued in every case due to the side effects.
As regards the degradation system of intracerebral Aβ, it has been reported that peptidase called neprilysin is a major enzyme responsible for degradation (non-patent documents 1, 2). Neprilysin is one kind of neutral endopeptidase present in various tissues of animals and is a membrane-bound enzyme having a catalytic site in the extracellular domain. It is known by in vitro experiments that enkephalin, substance P, atrial natriuretic peptide (ANP), gastrin releasing peptide (GRP), endothelin and the like can be a substrate for neprilysin.
The results correlating the progression of Aβ accumulation observed in normal aged brain and amyloid pathology in AD with a decrease in the intracerebral neprilysin level have been reported. The expression level markedly decreases with age in the cerebral cortex and hippocampus of normal mouse and AD model mouse. Recently, it has been revealed that a similar decrease occurs in human as well, and an inverse correlation between a decrease in the neprilysin level and the Aβ42 level of insoluble fraction has been reported.
Same results have also been reported by plural independent research groups on the decrease in the neprilysin levels in the AD brain. It is known that the expression level and the protein amount of neprilysin decrease by nearly 50% in the hippocampus and lateral lobe at pre-stage of AD. In the cerebellum which is resistant to amyloid pathology, the expression level of neprilysin is higher than in hippocampus and lateral lobe, and the expression of neprilysin does not decrease. On the other hand, in the autopsy brain with advanced amyloid pathology, the decrease in the neprilysin level is further strengthened and has been shown to drastically decrease by 70% that of the control group.
AD therapeutic drug focusing on the degradation system is expected to be a fundamental therapeutic drug for AD. At present, however, it is only in the stage of gene therapy of AD using the neprilysin gene being tried using a model mouse.
Polyphenol is well-known to have an antioxidant action, a cholesterol lowering action, an antibacterial action and the like, and thus generally known to exert a favorable influence on health maintenance. There are also reports that catechin, which is a polyphenol as a component derived from tea, is effective for AD (non-patent documents 3-5). It has been reported that (−)-epigallocatechin-3-O-gallate (EGCg), which is one kind of polyphenol and has the following structure
increases enzyme activity of neutral endopeptidase in nerve system cells (non-patent documents 6-9). Since general artificial substrates of neutral endopeptidase were used in the experiments thereof, it is unknown which enzyme was actually reacted on. Derivatives in which alkyl chain was added to EGCg to increase liposolubility (hydrophobicity) and bioavailability (absorption efficiency in the intestine and intracerebral transferability) have been reported (patent document 1, non-patent document 10). Amentoflavone, which is a polyphenol contained in ginkgo leaf and the like, has been reported to show inhibition of Aβ aggregation and cell death protective effect (non-patent documents 11, 12). Apigenin, which is a polyphenol contained in many plants, has also been reported to show an Aβ aggregation inhibitory effect (non-patent documents 13, 14). Kaempferol contained in strawberry and the like is also known to show inhibition of Aβ production, inhibition of Aβ aggregation, and cell death protective effect.
However, there is no paper showing the relationship between any polyphenol and neprilysin and it is not described or suggested that a more superior anti-AD effect can be obtained by derivatizing the polyphenol.
As enzymes that metabolize amyloid precursor protein (APP), α-, β- and γ-secretases are known. Aβ is produced by β- and γ-secretases, while α-secretase cleaves APP inside Aβ. When APP is metabolized by α-secretase, Aβ is not produced. Therefore, AD therapeutic drugs focusing on the enhancement of α-secretase activity are also expected.